1. Field of the Invention
The invention generally relates to bivalent ligands used for the treatment of neurological disorders such as those associated with AIDS. In particular, the invention provides bivalent ligands that contains two pharmacophores linked through a spacer, one of which interacts with the μ-opioid receptor (MOR) and the other of which interacts with the co-receptor CC chemokine receptor 5 (CCR5).
2. Background of the Invention
Since acquired immunodeficiency syndrome (AIDS) was identified three decades ago [69], the global prevalence of AIDS has stabilized at 0.8%, with over 33 million people infected with human immunodeficiency virus type-1 (HIV-1) as of 2007. Despite efforts to control the spread of this disease, the population of infected individuals continues to rise. After initial infection with HIV-1, neurovirulent strains targeting the co-receptor CC chemokine receptor 5 (CCR5) enter the central nervous system (CNS) within the first two weeks of infection and can occupy microglia, and to a lesser extent astroglia, to promote viral replication. Not only do these cells enhance pathogenesis by increasing the production of new virus, but their interactions with virus or shed viral proteins such as Tat and gp120 lead to activation and release of pro-inflammatory molecules such as oxyradicals and pro-inflammatory cytokines/chemokines, which, through bystander effects, cause neuronal damage and even death. Of the causes of HIV-1 infection, 10% of cases have been attributed to the contaminated needles of injection drug users (IDUs), and along with changes in risk behavior, the drug abusing population accounts for approximately ⅓ of HIV-1 infected individuals. Additionally, those with HIV-1 infection are more susceptible to abusing drugs. Co-morbid drug use of agents such as heroin, cocaine, and alcohol both accelerate progression to AIDS and complicate its treatment. Heroin abuse, in particular, has been shown to lead to a 4-fold increase in HIV-1 encephalitis (HIVE). Opioid drugs of abuse can synergistically increase both the inflammatory state of the CNS and neuronal damage/death through direct actions on μ-opioid receptor (MOR)-containing glia including astroglia, microglia, oligodendroglia, and glial precursors, and these coordinated responses create a cycle of inflammation whereby neuronal injury/death can occur. Opioids can also exert some direct effects on MOR-expressing neurons. Not only does opioid abuse influence inflammatory signaling, it also affects viral replication. MOR agonists including morphine, methadone, and DAMGO all increase the expression of CCR5, promoting replication of CCR5-utilizing strains, while these increases can be prevented with blockade of MOR by the inhibitors β-funaltrexamine, methylnaltrexone, and naltrexone.